Antigen Targeting to Human HLA Class II Molecules Increases Efficacy of DNA Vaccination

Abstract

It has been difficult to translate promising results from DNA vaccination in mice to larger animals and humans. Previously, DNA vaccines encoding proteins that target Ag to MHC class II (MHC-II) molecules on APCs have been shown to induce rapid, enhanced, and long-lasting Ag-specific Ab titers in mice. In this study, we describe two novel DNA vaccines that as proteins target HLA class II (HLA-II) molecules. These vaccine proteins cross-react with MHC-II molecules in several species of larger mammals. When tested in ferrets and pigs, a single DNA delivery with low doses of the HLA-II–targeted vaccines resulted in rapid and increased Ab responses. Importantly, painless intradermal jet delivery of DNA was as effective as delivery by needle injection followed by electroporation. As an indication that the vaccines could also be useful for human application, HLA-II–targeted vaccine proteins were found to increase human CD4+ T cell responses by a factor of ×103 in vitro. Thus, targeting of Ag to MHC-II molecules may represent an attractive strategy for increasing efficacy of DNA vaccines in larger animals and humans.

The Magnitude and IgG Subclass of Antibodies Elicited by Targeted DNA Vaccines Are Influenced by Specificity for APC Surface Molecules

“…Supporting such a view, the selective induction of IgG2a and Th1 responses induced by Xcl1 vaccines [(19, 21), results in this study] could be due to the exclusive expression of the Xcr1 receptor on cross-presenting cDC1 cells (28,29). By contrast, aMHCII-vaccine proteins most likely target many different types of MHCII + APCs, perhaps explaining induction of a mixed IgG1/ IgG2a response as well as a Th1/Th2 profile [ (8,13,30), results in this study]. Similarly, aCD11c and Flt3 vaccine proteins should target both cDC1 and cDC2, contributing to the observed mixed IgG1/IgG2a responses (31)(32)(33)(34).…”

Simultaneous Targeting of Multiple Hemagglutinins to APCs for Induction of Broad Immunity against Influenza

“…We have previously demonstrated that targeting of HA from H1N1 influenza viruses to MHCII molecules rapidly induced protective levels of neutralizing Abs in mice (18) and larger animals (21) and that APC-targeted DNA vaccines could be produced within 1 mo after identification of the viral sequence (28). In this article, we have demonstrated that this versatile and flexible format also contributed to improved Ab responses when extended to a mixture of six subtypes of influenza (H5, H6, H8, H9, H11, and H13).…”

“…Thus, the vaccine strategy could also confer some basic protection against an unexpected influenza emergence. To translate these results to humans, we have recently developed a targeting unit that is pan-specific for HLA class II molecules; this targeting unit should allow delivery of vaccine Ag to HLA class II molecules on APCs in all humans (21). Thus, the strategy presented in this article could be adapted to a clinical setting.…”

“…This could be chemokines that attract and activate leukocytes at the site of vaccine delivery (14) or perforin, which induces necrotic death (15). In another strategy, DNA has been constructed so that it encodes secreted fusion proteins that target Ags to APCs for enhanced immune responses (16)(17)(18)(19)(20)(21). This approach combines the attractiveness of DNA immunization with the well-known principle of APC targeting of Ag to increase Ag immunogenicity (22)(23)(24).…”

“…The increased efficacy conferred by MHCII targeting of Ag has recently been translated to influenza vaccination of ferrets and pigs (21). As a mechanism for enhanced Ab induction, it has been suggested that the DNA-encoded anti-MHCII-HA vaccine proteins bridge B cells and APCs in an APC-B cell synapse (16,27,28).…”